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Biotechnology in Fighting Fatal Disease – Cancer National Biotechnology Symposium 2012 Innovations in Biotechnology: From Education to Industry Sep 1, 2012, AMA, Ahmedabad Dr. Chirag Desai, MD, DM (Oncology) Hemato-oncology Clinic, Vedanta, Ahmedabad [email protected] Metastatic colon cancer (unresectable) 1970s – Only 5-FU – survival of 6 mths 1980s – Leucovorin/5-FU – survival of 9 mths Survival Increased 1990s – Only 5-FU – Addition of oxaliplatin/ Irinotecan/capecitabine - – survival of 18 mths 4 folds In 2000s – Avastin - – survival of 21 mths Now – Erbitux – survival of 25 mths 30 years Breast Cancer – stage II 1960s – Only surgery - 40% cured Cure Rate 1970s – CMF - 50% cured 1980s – CMF and Tamoxifen - 60% cured Doubled 1990s – Anthracyclines and taxanes - 67% cured In 40 2000s – Aromatase inhibitors - 73% cured years Now – Herceptin - 80% cured ?? Biotechnology in Cancer: Translational Research Bench to bedside The biological revolution of 20th century totally reshaped all fields of biomedical study -- cancer research being only one of them. Biotechnology helps in elucidating the normal cellular functioning And the derangements thereof resulting in disease Including cancer…….and The ways to tackle these derangements Chronic Myeloid Leukemia One cancer One chromosome One gene One Treatment Most Cancers Each cancer Multiple chromosomes Multiple genes Multiple Treatments Initiation Normal Cell Promotion Pre-Cancerous Cell Cancer Cell Signal transduction Migration Seed/Soil Immune Surveillance Invasion Angiogenesis Metastases Prevention/early detection Diagnosis/ prognosis Treatment Biotechnology techniques and processes (Evans, P. R. Biotechnology and Biological Preparations in Encyclopaedia of PT vol. 1, 3rd edn.) Growth Factor Growth Factor receptor Signal Transduction Research and development network Examples of Biologicals: Growth Factors: EGF VEGF FGF IGF PDGF Receptors: EGFR Her-2 VEGFR PDGFR ER/PR STIs: TKIs mTORI CDKI FTIs Others Mabs: Rituximab Avastin Herceptin Erbitux Biomab Providing Personalized Care in an Era of Molecular Medicine clinicaloptions.com/oncology Evolution From Empiric to Personalized Therapy in NSCLC Clinical Histologic Molecular Factors Agent Affected Asian, never-smoker, female Erlotinib, gefitinib Untreated CNS metastases, no hemoptysis, uncontrolled hypertension Bevacizumab Adenocarcinoma Erlotinib, gefitinib Nonsquamous Bevacizumab, pemetrexed Thymidylate synthase Pemetrexed EGFR mutation Erlotinib, gefitinib ERCC1/RRM1 Platinum RRM1 Gemcitabine KRAS mutation Erlotinib, gefitinib ↑ EGFR by FISH Erlotinib? Gefitinib? ↑ EGFR by IHC Cetuximab? EML4-ALK fusion Crizotinib Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:148-150. Patient Selection Improves Treatment Results in NSCLC No selection Molecular selection…. Clinical selection 28 Erlotinib alone >27 months Median survival (months) 24 20 16 12 8 4 BSC: 2–4 months Cisplatinbased regimens: 6–8 months Bevacizumab + platinum: >14 months Bevacizumab + platinumbased doublet: >12 months Pemetrexed + platinum: >12 months 8–10 months Nonsquamous Adenoonly Adenoonly 1990–2005 2005 2008 2008 Platinumbased doublets (3rd gen): EGFRmut+ 0 1970s 1980s 2009/10 VEGF in clinic Antibody – Bevacezumab (Avastin) Lung Cancer, Colon Cancer, Ovarian Cancer, Renal Cell Carcinoma, Brain Tumors, Breast Cancer Tyrosine kinase Inhibitors: Sunitinib, Sorafenib, Pazopinib, Axitinib, Dovitinib, others Renal Cell Cancer, Neuro-endocrine tumors, Liver cancers, GIST, Sarcoma Biologicals are effective in: Lung cancer Colon cancer Breast cancer Head and neck cancer Leukemias/Lymphomas Renal/Liver cancers Others Biologicals help in the treatment of >80% of cancers either curatively or in advanced cancers Challenges in the development of biologicals RBF Symposium Feb 2011 A Nobel Prize by Chance Start at the top 1. Formulate testable hypothesis 2. Make the plan / design the study Generate Hypothesis Design study Develop new theory Collect information Analyse and interprete finding Providing Personalized Care in an Era of Molecular Medicine clinicaloptions.com/oncology New Therapeutic Agent: Development Phases Biomarker Integration N = 30 Preclinical (~ 18 mos) Phase I (~ 18 mos) N = 300 Phase II (~ 18 mos) N = 1600 Phase III (~ 36 mos) Drug Approval Total Time ~ 90 mos or 7.5 yrs Phases of Development of New Biomarker linked to New Drug Confirm target Integrate biomarker Biomarker informative? Clinical validation Assay development Assay performance Assay performance Coprimary endpoint Gandara D, et al. NCI CAPR Workshop. 2011. Printed with permission. Clinical application of biomarker A large number of biologically/molecularly acting drugs are under development Traditional end points are less relevant New end points required OS still is a gold standard end point Surrogate end points need to be re-defined Even though response rate is less important, exact definition of response is critical Ongoing analysis of tissue/blood based biomarkers is critical Surrogate End points with targeted Therapies: Exploratory Traditional PFS QoL OS Pharmacoeconomics Others Target inhibition Tissue level Blood level Pharmacogenetic Tissue based Blood based Providing Personalized Care in an Era of Molecular Medicine clinicaloptions.com/oncology BATTLE: Phase II NSCLC Biomarker Study Umbrella protocol Core biopsy EGFR VEGF KRAS/BRAF RXR/CyclinD1 Biomarker profile Randomization: Equal Adaptive Erlotinib Equal (n = 25) Adaptive (n = 33) Vandetanib Equal (n = 23) Adaptive (n = 29) Erlotinib + Bexarotene Equal (n = 21) Adaptive (n = 15) Sorafenib Equal (n = 26) Adaptive (n = 72) Primary endpoint: 8-wk disease control rate; 30% assumed Kim ES, et al. AACR 2010. Abstract LBA1. Reprinted with permission. Providing Personalized Care in an Era of Molecular Medicine clinicaloptions.com/oncology BATTLE: Phase II NSCLC Biomarker Study—Discovery Platform Kim ES, et al. AACR 2010. Abstract LBA1. Reprinted with permission. Who should do this? •Academic institutions Generate Hypothesis •Corporate hospitals Design study Develop new theory Collect information Analyse and interprete finding •Individual practitioners •Medical associations •Collaborative effort Who should do this? Generate Hypothesis Design study Develop new theory Collect information Analyse and interprete finding Innovations [email protected] Future: Tests like Oncotype Dx21 in breast cancer Drugs like Imatinib in CML Outcome like sequential use of chemo and targeted drugs in myeloma Making cancer a chronic Disease